Asymmetric Synthesis of Spirocyclic Compounds

Spirocyclic compounds, characterised by two or more rings sharing a single quaternary carbon centre, have emerged as pivotal scaffolds in drug discovery and natural product synthesis. Their rigid three-dimensional architectures confer defined spatial arrangements, making them invaluable for probing biological targets and modulating physicochemical properties. Asymmetric synthesis of these frameworks centres on the controlled construction of stereogenic quaternary centres, often employing chiral catalysts—whether organocatalysts, transition-metal complexes or biocatalysts—to induce high levels of enantioselectivity. Common strategic approaches include enantioselective cycloadditions, Michael additions, and intramolecular ring-closing reactions. Recent advances address longstanding challenges such as ring strain management, step-economy and sustainability by adopting solvent-free conditions, mechanochemical activation and cascade processes. The integration of green chemistry principles has facilitated solvent reduction and operational simplicity, while mechanistic studies continue to unravel the factors governing stereocontrol. Practical applications span antiviral, anticancer and antimicrobial agents, with spirooxindoles, spiroketals and spiro[indole-pyrrolidine] derivatives standing out as prominent examples. This evolving field benefits from an interplay between method development and target-oriented synthesis, underscoring its global significance for the creation of complex, chiral molecules with precise three-dimensional shapes.

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Asymmetric Synthesis of Spirocyclic Compounds publication trend

The graph below shows the total number of articles in asymmetric synthesis of spirocyclic compounds across all publications each year (not limited to Nature Index journals).

Technical terms

Spirocyclic compound: A molecule containing two or more rings that share a single atom, typically a quaternary carbon, yielding a rigid three-dimensional framework.

Enantioselectivity: The preferential formation of one enantiomer over the other in a chiral reaction, commonly expressed as enantiomeric excess.

Organocatalysis: Catalysis achieved through small organic molecules that accelerate and direct chemical transformations without metals.

Mechanochemistry: The initiation of chemical reactions by mechanical force, often enabling solvent-free and energy-efficient processes.

References

1. Aqua/Mechanochemical Mediated Synthesis of Novel Spiro [Indole–Pyrrolidine] Derivatives. International Journal of Molecular Sciences (2023).
2. Stereoselective synthesis and applications of spirocyclic oxindoles. Organic Chemistry Frontiers (2021).
3. New Hybrid-type Squaramide-Fused Amino Alcohol Organocatalyst for Enantioselective Domino Michael Addition/Cyclization Reaction of Oxoindolines with Cyclic 1,3-Diketones. ACS Omega (2018).